1. Field of the Invention
The present invention is directed to compounds that are biaryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention is directed to phenyl or pyridyl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors wherein the phenyl or pyridyl group is at the 1-position and contains an aryl substituent group further optionally substituted.
2. Related Background
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3xe2x80x2, 5xe2x80x2-cyclic monophosphate, xe2x80x9ccAMPxe2x80x9d or xe2x80x9ccyclic AMPxe2x80x9d) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (xe2x80x9cPDExe2x80x9d) are a family of enzymes that metabolize 3xe2x80x2, 5xe2x80x2 cyclic nucleotides to 5xe2x80x2 nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 (xe2x80x9cPDE4xe2x80x9d, also known as xe2x80x9cPDE-IVxe2x80x9d), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (xe2x80x9cBurnoufxe2x80x9d), Ann. Rep. In Med. Chem., 33:91-109(1998). B. Hughes et al., Br. J. Pharmacol., 118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al., J. Med. Chem., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M. D. Houslay et al., Adv. In Pharmacol., 44:225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors. International Patent Publication WO9907704 describes 1-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.
A. H. Cook, et al., J. Chem. Soc., 413-417(1943) describes gamma-pyridylquinolines. Other quinoline compounds are described in Kei Manabe et al., J. Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al., J. Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J. Am. Chem. Soc., 114(17):6940-6941(1992).
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.
U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.
The present invention is directed to biaryl substituted 1,8-naphthyridin-4(1H)-ones represented by Formula (I): 
or pharmaceutically acceptable salts thereof, which are phosphodiesterase-4 inhibitors.
This invention also provides a pharmaceutical composition which includes an effective amount of the novel biaryl substituted 1,8-naphthyridin-4 (1H)-ones and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer""s disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues by the administration of an effective amount of the novel substituted 1,8-naphthyridin-4(1H)-ones or a precursor compound which forms in vivo the novel biaryl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors.
A compound of this invention is represented by Formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
Ar is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiadiazolyl, or imidazolyl, or oxides thereof when Ar is a heteroaryl;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In an embodiment of this one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C1-6alkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In another embodiment of this one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C3-6cycloalkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In still another embodiment of this one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R is H or xe2x80x94C1-6alkyl;
R1 is pyridyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In a second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridyl, pyrimidyl, or oxides thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In an embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridyl, pyrimidyl, or oxides thereof;
R is H;
R1 is H;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridyl, pyrimidyl, or oxides thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C1-6alkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In still another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridyl, pyrimidyl, or oxides thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C3-6cycloalkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-16alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In yet another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridyl, pyrimidyl, or oxides thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is pyridyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-16alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In a third aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is indolyl, quinolinyl, or oxides thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In an embodiment of the third aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is indolyl;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C1-6alkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-16alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In another embodiment of the third aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is quinolinyl or oxide thereof;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C1-6alkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-16alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In a fourth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is thienyl;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C -6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In an embodiment of the fourth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is thienyl;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C3-6cycloalkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In a fifth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridonyl;
R is H or xe2x80x94C1-6alkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, heteroaryl, or heterocycle group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
In an embodiment of the fifth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
Ar is pyridonyl;
R is H or xe2x80x94C1-6alkyl;
R1 is xe2x80x94C3-6cycloalkyl, optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, amino, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-16alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-16alkyl, or halogen substituents;
R2 is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycle, amino, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, amino, or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is H, OH, amine, halogen or C1-6alkyl, wherein the alkyl is optionally substituted with 1-6 independent halogen, OH, or amine substituents; and
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, or amine, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents.
As used herein, xe2x80x9calkylxe2x80x9d as well as other groups having the prefix xe2x80x9calkxe2x80x9d such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. xe2x80x9cAlkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and other like terms include carbon chains containing at least one unsaturated Cxe2x80x94C bond.
The term xe2x80x9ccycloalkylxe2x80x9d means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, xe2x80x9ccycloalkenylxe2x80x9d means carbocycles containing no heteroatoms and at least one non-aromatic Cxe2x80x94C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term xe2x80x9ccycloalkyloxyxe2x80x9d unless specifically stated otherwise includes a cycloalkyl group connected to the oxy connecting atom.
The term xe2x80x9calkoxyxe2x80x9d unless specifically stated otherwise includes an alkyl group connected to the oxy connecting atom.
The term xe2x80x9carylxe2x80x9d unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.
The term xe2x80x9caryloxyxe2x80x9d unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl, connected through the oxy connecting atom to the connecting site.
Ther term xe2x80x9cC0-C6alkylxe2x80x9d includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent or a direct bondxe2x80x94depending on whether the alkyl is a terminus or a bridging moiety.
The term xe2x80x9cheteroxe2x80x9d unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloC5alkyl is a five membered ring containing from 5 to no carbon atoms.
Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
The term xe2x80x9cheteroaryloxyxe2x80x9d unless specifically stated otherwise describes a heteroaryl group connected through an oxy connecting atom to the connecting site.
Examples of heteroaryl(C1-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
Examples of heterocycloC3-7alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
Examples of aryl(C1-6)alkyl include, for example, phenyl(C1-6)alkyl, and naphthyl(C1-6)alkyl.
Examples of heterocycloC3-7alkylcarbonyl(C1-6)alkyl include, for example, azetidinyl carbonyl(C1-6)alkyl, pyrrolidinyl carbonyl(C1-6)alkyl, piperidinyl carbonyl(C1-6)alkyl, piperazinyl carbonyl(C1-6)alkyl, morpholinyl carbonyl(C1-6)alkyl, and thiomorpholinyl carbonyl(C1-6)alkyl.
The term xe2x80x9caminexe2x80x9d unless specifically stated otherwise includes primary, secondary and tertiary amines.
Unless otherwise stated, the term xe2x80x9ccarbamoylxe2x80x9d is used to include xe2x80x94NHC(O)OC1-C4alkyl, and xe2x80x94OC(O)NHC1-C4alkyl.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine atoms.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, the substitution can be made at any of the groups. For example, substituted aryl(C1-6)alkyl includes substitution on the aryl group as well as substitution on the alkyl group.
The term xe2x80x9coxidexe2x80x9d of heteroaryl groups is used in the ordinary well-known chemical sense and include, for example, N-oxides of nitrogen heteroatoms.
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDxe2x80x9d), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
Dosage levels from about 0.001 mg/kg to about 140 mg/kg of body weight per day are useful in the treatment of conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer""s disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues which are responsive to PDE4 inhibition, or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 2.5 g per patient per day. Further, it is understood that the PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01 mg to about 1000 mg of the active ingredient, typically 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer""s disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissuesxe2x80x94maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cCAMP levelsxe2x80x94by the administration of an effective amount of the compounds of this invention. The term xe2x80x9cmammalsxe2x80x9d includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
Further, as described above, the compound of this invention can be utilized in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) H1 (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-xcex1 and LTB4. Upon stimulation with LPS, activated monocytes express and secrete TNF-xcex1 up to 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-xcex1 by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, by using the same blood sample, it is possible to evaluate the potency of a compound on two surrogate markers of PDE4 activity in the whole blood by the following procedure.
Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. 500 xcexcL aliquots of blood were pre-incubated with either 2 xcexcL of vehicle (DMSO) or 2 xcexcL of test compound at varying concentrations for 15 minutes at 37xc2x0 C. This was followed by the addition of either 10 xcexcL vehicle (PBS) as blanks or 10 xcexcL LPS (1 xcexcg/mL final concentration, #L-2630 (Sigma Chemical Co., St. Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37xc2x0 C., another 10 xcexcL of PBS (blank) or 10 xcexcL of LPS (1 xcexcg/mL final concentration) was added to blood and incubated for 30 minutes at 37xc2x0 C. The blood was then challenged with either 10 xcexcL of PBS (blank) or 10 xcexcL of fMLP (1 xcexcM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37xc2x0 C. The blood samples were centrifuged at 1500xc3x97 g for 10 minutes at 4xc2x0 C. to obtain plasma. A 50 xcexcL aliquot of plasma was mixed with 200 xcexcL methanol for protein precipitation and centrifuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to the manufacturer""s procedure. TNF-xcex1 was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) according to manufacturer""s procedure. The IC50 values of Examples 1 to 76 generally ranged from 0.005 xcexcM to 15.4 xcexcM.
Compounds of the invention have been tested for effects on an IgE-mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, animals were challenged with aerosolized ovalbumin while under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48 h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.
Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV cAMP-specific phosphodiesterases were screened in a 96-well plate format as follows:
In a 96 well-plate at 30xc2x0 C. was added the test compound (dissolved in 2 xcexcL DMSO), 188 mL of substrate buffer containing [2,8-3H] adenosine 3xe2x80x2,5xe2x80x2-cyclic phosphate (cAMP, 100 nM to 50 xcexcM), 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 mL of human recombinant PDE4 (the amount was controlled so that xcx9c10% product was formed in 10 min.). The reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, N.J.). The product AMP generated was quantified on a Wallac Microbeta(copyright) 96-well plate counter (EGandG Wallac Co., Gaithersburg, Md.). The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point titration.
The IC50 values of Examples 1 to 76 were determined with 100 nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system. The IC50 values of Examples 1-76 generally ranged from 0.1 nM to 14.8 nM, although six examples had an IC50 value between 34.3 and 134.0 nM.
The examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperaturexe2x80x94that is, at a temperature in the range of 18-25xc2x0 C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60xc2x0 C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and xe2x80x9cdxe2x80x9d indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (xcex4) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, xe2x80x9cArxe2x80x9d signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)),mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles),mmol (millimoles), eq (equivalent(s)).
Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula I except where defined otherwise.
In a first method outlined in Scheme 1 below, an appropriately substituted derivative of ethyl 2-chloronicotinoyl acetate of formula II is reacted with 1.5 equivalents of triethyl orthoformate and 5 equivalents of acetic anhydride at 130xc2x0 C., and after removal of the volatile components, the crude 2-chloronicotinoyl acrylate of formula III is immediately reacted with 1.2 equivalents of an appropriately substituted haloaryl amine of formula IV, such as, for example 3-bromoaniline, in a halogenated hydrocarbon solvent such as methylene chloride at a temperature of 0xc2x0 C. to room temperature. After an appropriate reaction time ranging from 2 to 24 hours the resulting 3-arylamino acrylate of formula V is obtained by evaporation of the solvent and may be further purified by chromatography on silica gel or crystallization from an appropriate solvent.
The compound of formula V may alternatively be used without further purification in the following step. Cyclization of the compound of formula V to the 1-haloaryl-1,4-dihydro[1,8]naphthyridin-4-one carboxylate of formula VI is effected by treatment with a small excess of a strong base such as an alkali metal hydride, for example sodium hydride, in an appropriate solvent such as tetrahydrofuran at a starting temperature of 0xc2x0 C. with warming to room temperature if required to complete the process. The product of formula VI is isolated in crude form by dilution with a large volume of water followed by filtration or by extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration.
The product of formula VI thus obtained can be hydrolyzed to the corresponding carboxylic acid derivative under basic conditions, using an aqueous solution of an alkali base such as an alkali carbonate or preferably sodium or potassium hydroxide, with an organic cosolvent such as tetrahydrofuran or a primary, secondary or tertiary alkanol, such as methanol or ethanol, or a combination thereof at temperatures ranging from room temperature to reflux temperature for the appropriate time. The resultant carboxylic acid is isolated in crude form following acidification using an aqueous solution of an inorganic acid such as hydrochloric, sulfuric or a similar acid, and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration.
The carboxylic acid is then transformed into the appropriate primary, secondary or tertiary amide analog of formula VII by any general procedure well known to the organic chemist, preferably via initial transformation into a mixed anhydride by treatment with a small excess, such as 1.25 equivalents, of an appropriate alkyl chloroformate such as ethyl or isobutyl chloroformate, in the presence of a larger excess, such as 2.5 equivalents, of a tertiary organic amine such as triethylamine or N,N-diisopropylethylamine in an organic solvent such as tetrahydrofuran at low temperature, preferably 0xc2x0 C., for a period of 30 minutes to 3 hours. An excess, usually 5 or more equivalents, of an appropriate primary or secondary amine or of an aqueous solution of ammonium hydroxide is then added and the resulting reaction is allowed to proceed at a temperature ranging from 0xc2x0 C. to room temperature for an appropriate length of time, usually 1-24 hours.
The desired amide of formula VII is then isolated in crude form by precipitation with water and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration. In cases where the amide moiety is 2,6-dichloropyridin-4-yl, a different procedure is used in which the anion of 4-amino-3,5-dichloropyridine is generated at low temperature, preferably at 0xc2x0 C., using a strong alkali hydride such as sodium hydride in a solvent such as tetrahydrofuran, and reacted with the acid chloride of a carboxylic acid (from hydrolysis of an ester of formula VI) generated by an appropriate known procedure, usually by the action of oxalyl chloride activated by a catalytic amount of N,N-dimethylformamide in a solvent such as tetrahydrofuran.
The amides of general formula VII are processed into the products of formula I by reaction with an appropriately substituted aryl or heteroaryl boronic acid or boronate ester of formula VIII under the catalysis of a transition metal species such as trans-dibromobis(triphenylphosphine)palladium (II) or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in an appropriate solvent or solvent mixture, preferably a 1:1 mixture of toluene and ethanol in the presence of an excess of an aqueous solution of an alkali base such as sodium carbonate, at an appropriate temperature, preferably 50 to 100xc2x0 C., for an appropriate length of time ranging from 0.5 to 48 hours.
The resulting reaction product is then isolated in crude form by precipitation with water and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration.
Compounds of formula I may also be obtained by reaction of a compound of formula VII with an appropriately substituted aryl or heteroaryl tributyl stannane of formula IX under the catalysis of a transition metal species such as trans-dibromobis(triphenylphosphine)palladium (II) or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a copper (I) species such as cuprous iodide an appropriate solvent such as N,N-dimethylformamide at a temperature range of 50-100xc2x0 C. for a period of 2 to 24 hours. Isolation of the reaction product is effected as described above.
Alternatively, an ester of formula VI can be processed into an ester of formula X by reaction with an appropriately substituted boronic acid or boronate ester, or with an appropriately substituted stannane derivative under the conditions described above, and the ester can be hydrolyzed and transformed into an amide of formula I.
The boronic acids of formula VIII or corresponding boronate esters are usually obtained from commercial sources. Where required, they can be prepared readily from the corresponding halides via metallation with n-butyllithium followed by reaction with a trialkyl borate, or by using classical transition metal-catalyzed coupling procedures using diboron pinacol ester. The stannanes of formula IX are generated from the corresponding halides via initial metallation using n-butyllithium followed by addition of tributyltin chloride. 
In an alternative method for the preparation of compounds of formula I, outlined in Scheme 2 below, an amide of formula VII can be transformed into a corresponding boronate ester of formula XI by treatment with an excess of diboron pinacol ester in the presence of an inorganic salt such as potassium acetate under the catalysis of a transition metal species such as trans-dibromobis(triphenylphosphine)palladium (II) or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a solvent such as N,N-dimethylformamide at temperatures ranging from 50 to 100xc2x0 C. for a length of time ranging from 1 to 48 hours. The boronate of formula XI may be isolated by precipitation with water and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The resulting product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration.
Alternatively, the boronate of formula XI can be used as generated in situ in the reaction medium without isolation, and reacted with a small excess of an appropriately substituted aryl or heteroaryl halide of formula XII under the catalysis of a transition metal species such as [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in an appropriate solvent or solvent mixture, preferably a 1:1 mixture of toluene and ethanol in the presence of an excess of an aqueous solution of an alkali base such as sodium carbonate, at an appropriate temperature, preferably 50 to 100xc2x0 C. for an appropriate length of time ranging from 0.5 to 48 hours.
The reaction product of formula I is then isolated in crude form by precipitation with water and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration. 
In a third method used for the synthesis of compounds of formula I of this invention (scheme 3), an intermediate nicotinoyl acrylate of formula III is reacted with an appropriately constructed diaryl or heteroarylaryl amine of formula XII under the conditions described previously to afford a compound of formula XIV which is cyclized by the action of a strong base such as sodium hydride as described above to afford an ester of formula X which is processed into a compound of formula I via hydrolysis and amide formation as described above. 
The diaryl or heteroarylarylamine intermediates of formula XIII were assembled as indicated in Scheme 4. An appropriately substituted aniline boronic acid of formula XV is coupled with an appropriately substituted aryl or heteroaryl halide of general formula XII under the catalysis of a transition metal species as described above to afford the formula XIII compounds used in Scheme 3. 
Bromopyridine intermediates substituted at the 2-position by carbon based nucleophiles of formula XVII, where R8 is selected from R2 moieties having a carbonxe2x80x94carbon link to the pyridine, are conveniently prepared as shown in Scheme 5. The bromopyridine intermediates are prepared from dihalides of formula XVI by treatment with an appropriate solution of a Grignard reagent under the catalysis of a transition metal species such as [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloronickel (II) in a solvent such as tetrahydrofuran at a temperature range of xe2x88x9210xc2x0 C. to room temperature and the resulting reaction mixture worked up by well known procedures to afford the desired product. 
Halopyridine intermediates of type XVIII where the 2-substituent is an alkoxy group OR9 are derived from dihalides of formula XVI by displacement with an appropriate alkali alkoxide as outlined in scheme 6. The reaction is effected in a solvent such as N,N-dimethylformamide at a temperature range of 0xc2x0 C. to room temperature and, upon completion of the reaction, the products are isolated and purified following classical procedures. 
Where intermediates of formula XIX or XX in which the 2-substituent is sulfide, sulfoxide or sulfone were required, they were attained as described in Scheme 7. An appropriate dihalopyridine of type XVI is reacted with an appropriate thioalkoxide, usually generated from the corresponding thiol or disulfide through the action of a strong base such as an alkali hydride or n-butyllithium, in a solvent such as N,N-dimethylformamide or diethyl ether at a temperature range of xe2x88x9278xc2x0 C. to room temperature. Upon completion of the reaction the products of formula XIX are isolated and purified following classical procedures. The products thus obtained can be oxidized to the corresponding sulfoxides or sulfones of formula XX through the action of an oxidizing agent such as oxone or an organic peracid. In Scheme 7, R10 is H or C1-6alkyl. 
The preparation of haloacyl pyridine intermediates of formula XXII, presented in Scheme 8, requires treatment of a halopyridine ester of type XXI with a solution of an appropriate Grignard reagent in a solvent such as diethyl ether at a temperature range of 0xc2x0 C. to room temperature. If the reaction is carried out for a longer period or under reflux a halopyridine carbinol of formula XXIII is obtained. In Schemes 8 and 9, R7 is C1-6alkyl and R6 is methyl or ethyl. 
Scheme 9 outlines an alternative sequence for the synthesis of certain halopyridine carbinols of type XXIII. When 2,5-dibromopyrine is treated with n-butyllithium in toluene at xe2x88x9278xc2x0 C. followed by addition of an appropriate ketone or aldehyde and subsequent quenching at xe2x88x9278xc2x0 C., a carbinol of type XXIII results where the carbinol group occupies the 2-position of the pyridine ring. If the metallation step is performed in diethyl ether, the same process leads to an intermediate of formula XXIII in which the carbinol group occupies the 5-position of the pyridine ring. 
Scheme 10 demonstrates the methods of synthesis for compounds of formula I in which R2 is a substituted phenyl or heteroaryl group. An intermediate compound of Type I where R2 is a halogen is reacted with an appropriately substituted boronic acid or boronate ester of formula VII or tributyl stannane of formula IX using one of the methods described above to afford the desired compound. 
Various further transformations on pre-assembled compounds of formula I are illustrated in Scheme 11. In cases where the Ar group is a pyridine or quinoline group it can be oxidized to the corresponding nitrogen oxide by the action of an appropriate oxidizing agent such as m-chloroperioxybenzoic acid or magnesium monoperoxyphthalate under commonly used conditions. In cases where one or more of the substituents on the Ar group is a ketone it is conveniently transformed into an oxime analog through the action of hydroxylamine in pyridine as solvent. A sulfide substituent is easily oxidized to the corresponding sulfoxide or sulfone derivative by using an appropriate quantity of an oxidant such as oxone or an organic peracid.
The transformation of a 2-benzyloxypyridine into the corresponding 2-pyridone was accomplished by treatment with trifluoroacetic acid in a solvent such as methylene chloride at room temperature or under slight warming. The removal of a tert-butyloxycarbonyl protecting group from a piperazine ring is effected by reaction with trifluoroacetic acid in a solvent such as 1,2-dichloroethane at reflux temperature. In examples where a substituent on Ar is a hydroxymethyl group it can be derivatized to the analogous halomethyl moiety using a tetrahalomethane in the presence of a trisubstituted phosphine such as triphenylphosphine or diphos in a solvent such as methylene chloride. The halide can be displaced by an appropriate sulfinic acid sodium salt to afford the alkyl or arylsulfonylmethyl analog. 
The transformation of a 1-hydroxy-1-methylalkyl derivative such as exemplified by compounds of type XXIV of scheme 12 into 1,2-dihydroxyalkyl analogs of type XXVI is effected via initial acid-catalyzed dehydration, for example by heating in aqueous sulfuric acid, to afford an intermediate 1-alkylvinyl species of type XXV which is transformed into the desired diol XXVI by a dihydroxylation process, using for example an oxidant such as 4-methylmorpholine N-oxide (NMO) in the presence of a catalytic quantity of potassium osmate dihydrate. 